Clinical Policy Title: Spinraza

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1 Clinical Policy Title: Spinraza Clinical Policy Number: Effective Date: July 1, 2018 Initial Review Date: May 19, 2017 Most Recent Review Date: June 5, 2018 Next Review Date: June 2019 Related policies: Policy contains: Spinal muscular atrophy. Antisense oligonucleotide therapy. Spinraza (Nusinersen; Biogen, Research Triangle Park, North Carolina). None. ABOUT THIS POLICY: Prestige Health Choice has developed clinical policies to assist with making coverage determinations. Prestige Health Choice s clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer-reviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of medically necessary, and the specific facts of the particular situation are considered by Prestige Health Choice when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. Prestige Health Choice s clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. Prestige Health Choice s clinical policies are reflective of evidencebased medicine at the time of review. As medical science evolves, Prestige Health Choice will update its clinical policies as necessary. Prestige Health Choice s clinical policies are not guarantees of payment. Coverage policy Prestige Health Choice considers the use of Spinraza (nusinersen) to be clinically proven and, therefore, medically necessary when all of the following criteria are met (Center for Drug Evaluation and Research, 2016; Chiriboga, 2016; Finkel, 2016; Hache, 2016; Luu, 2017): Member has a clinical diagnosis of spinal muscular atrophy types 1, 2, or 3. Member has a genetic confirmation of spinal muscular atrophy from a molecular genetic test with mutation analysis documenting a genetic deletion or mutation of the exon 7 of the 5q spinal muscular atrophy survival motor neuron 1 (SMN1) gene. The drug is prescribed by a neurologist. Documentation submitted with the request of baseline motor function or motor milestone achievement by one of the following: Children s Hospital of Pennsylvania Infant Test of Neuromuscular Disorders (CHOP- INTEND) for spinal muscular atrophy type 1. 1

2 - Hammersmith Functional Motor Scale Expanded Scores (HFMSE) or Hammersmith Infant Neurological Examination section 2 (HINE-2) for spinal muscular atrophy types 2 and 3. Baseline laboratory values (within 30 days of request) for the following laboratory tests: - Complete blood count. - Prothrombin time and activated partial thromboplastin time. - Spot urine protein test. The member is receiving comprehensive treatment based on standards of care for spinal muscular atrophy. The request is for a U.S. Food and Drug Administration approved dose. Prestige Health Choice considers reauthorization of Spinraza to be medically necessary when all of the following criteria are met: The member is receiving comprehensive treatment based on standards of care for spinal muscular atrophy. Spinraza is prescribed by a neurologist. The request is for an Food and Drug Administration approved dose. Documentation of clinical response based on provider s assessment is submitted with the request (e.g., improvement in motor function/motor milestone achievement scores using CHOP-INTEND, HFMSE or HINE, improvement in more categories of motor milestones than worsening, or patient remains permanently ventilator-free). CHOP-INTEND responder is defined as 4-point change from baseline. HINE-2 responder is defined as 2-point increase (or maximal score of 4) in ability to kick (consistent with improvement by at least 2 milestones), or 1-point increase in the motor milestones of head control, rolling, sitting, crawling, standing, or walking (consistent with improvement by at least one milestone); the member must exhibit improvement in more categories of motor milestones than worsening. HFMSE responder (scored as 0, 1, or 2 with maximum of 40) is defined as 3-point increase in score from pretreatment baseline. Documentation of the following laboratory tests within 30 days of request: - Complete blood count. - Prothrombin time and activated partial thromboplastin time. - Spot urine protein test. Limitations: Coverage determinations are subject to benefit limitations and exclusions as delineated by the state Medicaid authority. The Florida Medicaid website may be accessed at Physician/clinical reviewer must override criteria when, in their professional judgment, the requested item is medically necessary. 2

3 If all of the conditions are met, an initial authorized request will be covered for five doses (four loading doses and the first maintenance dose).reauthorizations will be for 12 months. If the conditions are not met, the request will be sent to a medical director/clinical reviewer for medical necessity review. Contraindications to Spinraza include the presence of any medical condition that would affect patient safety or the ability to carry out lumbar puncture procedures or outcome measure testing, for example: Untreated or inadequately treated active infection. History of brain or spinal cord disease or abnormalities, tumors, severe contractures, or severe scoliosis. Implanted shunt for the drainage of cerebrospinal fluid (CSF) or an implanted central nervous system (CNS) catheter. History of bacterial meningitis. Prior injury (e.g., upper or lower limb fracture) or surgical procedure from which the subject has not fully recovered or achieved a stable baseline. Alternative covered services: Supportive care consistent with standards of care for spinal muscular atrophy. Background Spinal muscular atrophy is a group of genetic disorders characterized by degeneration of anterior horn cells in the spinal cord and brain stem, resulting in muscle atrophy and weakness (Hoy, 2017). Spinal muscular atrophy affects one in 6,000 to one in 10,000 people (Genetics Home Reference [GHR], 2017). It is the most common genetic cause of infant mortality. Several genetic mutations have been implicated in spinal muscular atrophy. The vast majority of cases results from deletion or mutation of the SMN gene on chromosome 5q13. The SMN gene is responsible for SMN protein production, which plays a critical role in motor neuron maintenance throughout the body. The SMN gene exists in two forms: SMN1 and SMN2 (Kolb, 2015). Typically, individuals have two copies of the SMN1 gene and at least two copies of the SMN2 gene. SMN1 and SMN2 copies are nearly identical and encode the same protein. The structural difference between them is the absence of a single nucleotide in exon 7 on the SMN2 gene. This nucleotide is thought to be an exon splice enhancer responsible for cutting out sections of DNA that do not code for the protein (introns) and combining the coded portions (exons) to form a mature messenger RNA molecule that is then translated into SMN protein. The SMN1 gene produces most of the functional full-length SMN protein, whereas the SMN2 gene produces smaller amounts in a less stable form. Deletions or mutations in both copies of the SMN1 gene (homozygous deletion) force greater reliance on the SMN2 gene for SMN protein production, resulting in insufficient (but not absent) levels of the SMN protein and subsequent motor neuron loss (Hoy, 2017; Kolb, 2015). Mutations in SMN2 alone do not lead to disease, but the number of extra copies of the SMN2 gene is the primary determinant of disease severity of spinal muscular atrophy (GHR, 2017; Kolb, 2015). 3

4 Other genes associated with spinal muscular atrophy are the ubiquitin-like modifier activating enzyme 1 (UBAI), dynein cytoplasmic 1 heavy chain 1 (DYNC1H1), and VAMP-associated protein B and C (VAPB) genes. The UBAI gene is involved in protein degradation within cells. The DYNC1H1 gene is necessary for protein transport, intracellular mobility, and many other cell processes. VAPB function is less understood but is associated with endoplasmic reticulum function that prepares proteins for intracellular transport (Kolb, 2015). Clinical features of spinal muscular atrophy: Most forms of spinal muscular atrophy are SMN deficiency-related with resultant voluntary muscle weakness and wasting of proximal muscles. Other less common forms of spinal muscular atrophy unrelated to SMN deficiency initially affect mostly the distal muscles. In both forms cognition may be normal. An accumulating body of evidence suggests other non-motor neuron cells may be involved in spinal muscular atrophy development, such as astrocytes, microglia, and sensory neurons within the CNS, and Schwann cells and muscle cells outside of the CNS; SMN deficiency may impact bone, pancreas, liver, and cardiac function (Simone, 2016). The clinical manifestations and disease severity of spinal muscular atrophy are highly variable (Wang, 2007). There is a higher prevalence of feeding and swallowing difficulties, gastrointestinal dysfunction, hip subluxation, kyphoscoliosis, difficulty coughing, joint contractures, and voice/speech problems, particularly among patients with more severe disease. Pulmonary disease is the major cause of morbidity and mortality in spinal muscular atrophy types 1 and 2 (Wang, 2007). The number of extra SMN2 copies is the primary determinant of spinal muscular atrophy clinical severity, but other genetic modifiers contribute to the variability even within phenotypes (Kolb, 2015). Disease phenotypes are classified according to a scheme developed at the 1991 International Consortium on Spinal Muscular Atrophy sponsored by the Muscular Dystrophy Association; these phenotypes were modified into six subtypes on the basis of age of onset, inheritance pattern, and maximum motor function achieved (Kolb, 2015; Munsat, 1991): Spinal muscular atrophy type 0 Neonate presents with severe weakness and hypotonia with a history of decreased fetal movements, areflexia, facial diplegia, atrial septal defects, and joint contractures. Spinal muscular atrophy type 1 Infant presents with hypotonia, poor head control, and reduced or absent tendon reflexes prior to 6 months of age, unable to sit unassisted (also known as Werdnig-Hoffman disease). Type 1 accounts for approximately 60 percent of all patients with spinal muscular atrophy. Spinal muscular atrophy type 2 Child is able to sit unassisted at some point during their development, but never walk independently. It manifests as progressive proximal leg weakness that is greater than weakness in the arms, and the presence of hypotonia and areflexia. 4

5 Spinal muscular atrophy type 3 Child or adult is able to walk unattended at some point during their lifetime. It may be classified further as type 3a (18 months to 3 years of age) and type 3b (> 3 years old) (also known as Kugelberg-Welander disease). Spinal muscular atrophy type 4 In adults only, it represents < 5 percent of spinal muscular atrophy cases and is the mildest form of the disease. Diagnostic delay is common in spinal muscular atrophy, and length of delay typically varies by spinal muscular atrophy type (Lin, 2015). Assessing motor skills of patients with spinal muscular atrophy, particularly children with more severe disease, can be challenging. Standard motor assessment tools for infants often rely on prone and head control items and are poorly tolerated, or they are not sufficiently sensitive to capture the motor skills in this population. The HINE-2 motor milestone achievement score was developed for infants ages 2 to 24 months, but not specifically for spinal muscular atrophy, nor has it been validated in spinal muscular atrophy populations. Three measures have been developed and validated specifically for spinal muscular atrophy populations: The CHOP INTEND for patients with spinal muscular atrophy type I and either two or three copies of SMN2 (Glanzman, 2011). HFMS for patients with spinal muscular atrophy types 2 or 3 (Main, 2003). HFMSE for ambulatory patients with spinal muscular atrophy types 2 or 3 (O Hagen, 2007). Treatment: Spinal muscular atrophy is associated with multiple clinical problems that affect respiratory, nutritional, orthopedic, rehabilitative, emotional, and social aspects of the disease. Current standard treatment is not curative, but focuses on supportive and preventive measures that address the effects of muscle weakness and related clinical problems that develop with age (Wang, 2007). Drug treatment for spinal muscular atrophy types 1, 2, and 3 has not shown significant clinical efficacy in robust clinical trials (Wadman, 2012a; Wadman, 2012b). Knowledge of the genetic pathophysiology of spinal muscular atrophy and motor neuron development has consequences for potential novel treatments for spinal muscular atrophy (Farrar, 2015). Potential treatment for spinal muscular atrophy applies new biologically active molecules that target the nucleic acids involved in protein expression (Sardone, 2017). Antisense oligonucleotides are synthetic singlestranded strings of nucleic acids that bind to precursor ribonucleic acid (pre-rna) or messenger RNA (mrna) to interfere with gene splicing, regulation of protein translation, or RNA/protein binding. The goal is to manipulate the SMN2 gene to produce higher amounts of functional SMN protein and correct the fundamental defect in spinal muscular atrophy (Tisdale, 2015). In 2016, the Food and Drug Administration approved the first new CNS-targeted oligonucleotide-based therapy for spinal muscular atrophy under the Food and Drug Administration Orphan Drug Designation 5

6 program (ODDP) 1. Nusinersen (ISIS ) was approved based on the results of several safety and efficacy studies (National Library of Medicine, 2018). Nusinersen modulates the splicing of the SMN2 mrna transcript to include exon 7, thereby increasing the production of full-length, more stable SMN proteins. Antisense oligonucleotides display unique pharmacodynamics and pharmacokinetic properties that can adversely impact treatment safety, efficacy, and route of delivery. Nusinersen is available commercially as Spinraza. Spinraza is approved for intrathecal use in pediatric and adult patients with spinal muscular atrophy. Antisense oligonucleotides are unable to cross an intact blood brain barrier when delivered systemically, but intrathecal injection of Spinraza into the CSF allows the drug to be distributed within the CNS and peripheral tissues. The mean terminal elimination half-life is estimated to be 135 to 177 days in CSF, and 63 to 87 days in plasma. Spinraza is excreted by the kidneys. The manufacturer recommends four loading doses at 12 mg (5 ml) per dose and a maintenance dose administered once every four months thereafter (Food and Drug Administration, 2017). Searches Prestige Health Choice searched PubMed and the databases of: UK National Health Services Centre for Reviews and Dissemination. Agency for Healthcare Research and Quality s National Guideline Clearinghouse and other evidence-based practice centers. The Centers for Medicare & Medicaid Services (CMS). We conducted searches on April 26, Search terms were: antisense oligonucleotide, spinal muscular atrophy, Muscular Dystrophies [Mesh], Spinraza, nusinersen, Spinal Muscular Atrophies of Childhood [Mesh], Muscular Atrophy, Spinal [Mesh], Muscular Disorders, Atrophic [Mesh], and Survival of Motor Neuron 1 Protein [Mesh]. We included: Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidence-grading hierarchies. Guidelines based on systematic reviews. Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies), reporting both costs and outcomes sometimes referred to as efficiency studies which also rank near the top of evidence hierarchies. 1 The Orphan Drug Designation program provides orphan status to drugs and biologics that either: 1) provide the safe and effective treatment, diagnosis, or prevention of rare diseases/disorders that affect fewer than 200,000 people in the U.S.; or 2) affect more than 200,000 persons but are not expected to recover the costs of developing and marketing a treatment drug (FDA, 2017). 6

7 Findings The evidence for this policy comprises data from: an overview of phase III clinical trials submitted to the Food and Drug Administration for approval (Center for Drug Evaluation and Research, 2016); four peerreviewed articles of the pharmacokinetics (PKs), safety, and preliminary efficacy of nusinersen from phase I and II clinical trials (Chiriboga, 2016; Finkel, 2016; Hache, 2016; Luu, 2017); and three conference presentations (De Vivo, 2017; Kuntz, 2017; Mercuri, 2017). Patients enrolled in the studies had clinical or molecular genetic diagnosis consistent with spinal muscular atrophy with a SMN1 genetic deletion or mutation and typically at least two copies of the SMN2 gene. The majority of enrollees had spinal muscular atrophy types 1 and 2 without abnormalities on diagnostic imaging that would interfere with the lumbar puncture procedures or CSF circulation. Motor function scores were measured at baseline and follow up. Safety: Administration of multiple intrathecal doses of nusinersen showed acceptable safety, tolerability, and pharmacology consistent with its intended mechanism of action. Plasma and CSF levels of nusinersen are dose-dependent with a prolonged CSF drug half-life of four to six months after initial clearance (Chiriboga, 2016; Luu, 2017). Although a PK modeling study showed that age-based dosing in children ages < 2 years ensured a more comparable drug exposure relative to a fixed dosing scheme, no dose-limiting toxicity had been reported in any of the trials from which the data were derived; as a result, the investigators recommended a fixed-dose scheme of 12 mg across all age groups (Luu, 2017). Analysis of autopsy tissue showed nusinersen uptake at therapeutic concentrations in motor neurons throughout the spinal cord and neurons and other cell types in the brainstem and other brain regions, increased SMN2 mrna exon 7 inclusion, and SMN protein concentrations in the spinal cord (Finkel, 2016). The Food and Drug Administration supports a 12mg/5mL dose of nusinersen across age groups, as the average CSF volume overlaps between children and adults (Center for Drug Evaluation and Research, 2016). No significant immunogenic response to a single intrathecal dose of nusinersen was observed at nine to 14 months follow up (Chiriboga, 2016). The ability of anti-drug antibodies to cross-react with nucleic acids was not evaluated. The investigators and Food and Drug Administration recommended a post-marketing requirement to assess for the presence of antibodies that bind native double-stranded DNA among patients treated with nusinersen (Center for Drug Evaluation and Research, 2016). Adverse events, including serious adverse events, were either not related, or unlikely related, to nusinersen and resolved with conservative treatment (Chrirboga, 2016; Hache, 2016). The most commonly reported adverse events were related to the lumbar puncture headache, back pain, vomiting, and post-lumbar puncture syndrome at a rate comparable to other pediatric populations, and most occurred within 72 hours after the procedure. Adverse events were more frequent in older children, children with type 3 spinal muscular atrophy, and use of larger needles (Hache, 2016). Although lumbar punctures are not typically performed in persons with spinal muscular atrophy, these results suggest that a lumbar puncture can be performed successfully in this population. 7

8 The Food and Drug Administration identified infrequent, but potentially significant, safety issues with nusinersen (Center for Drug Evaluation and Research, 2016). These included thrombocytopenia after lumbar puncture, hyponatremia, effect on growth, rash, possible vasculitis, and hepatic, renal, cardiac, and neurologic effects. None of these safety issues would preclude the beneficial effects of treatment. The Food and Drug Administration recommended that risk management of nusinersen can be accomplished through appropriate labeling and enhanced pharmacovigilance for thrombocytopenia, glomerulonephritis, nephrotic syndrome, or nephrotic range proteinuria. To that end, Food and Drug Administration recommends testing at baseline and before each dose for signs of thrombocytopenia, coagulation abnormalities, and renal toxicity. The Food and Drug Administration recommended further pre-clinical research into carcinogenic effects and pre-and post-natal development including maternal function (Center for Drug Evaluation and Research, 2016). Efficacy: A summary review of studies of ISIS CS3B (the ENDEAR trial) and ISIS CS4 (the CHERISH trial) assessed the interim efficacy data on which Food and Drug Administration approval was based (Center for Drug Evaluation and Research, 2016). ENDEAR was a multisite, randomized, double-blind, shamcontrolled trial of patients with spinal muscular atrophy type 1 and two copies of the SMN2 gene. CHERISH was a 15-month, double-blind, sham-controlled trial in patients with spinal muscular atrophy type 2 or 3 in children ages two through 12 years. The manufacturer provided additional supportive data to the Food and Drug Administration from open-label studies that enrolled a broad age range of patients with spinal muscular atrophy. Interim ENDEAR trial results showed that a significantly greater percentage of nusinersen-treated infants achieved a motor milestone response compared to controls (40 percent versus 0 percent; p<0.0001) as measured by HINE. Five patients in the nusinersen group were able to sit unassisted compared to no patients in the control group. According to the investigators, this would be an extremely rare milestone in patients diagnosed with spinal muscular atrophy type 1, although it is possible that some of those patients could have had spinal muscular atrophy type 2. A smaller percentage of nusinersen-treat patients either died or required permanent ventilation than controls (34percent versus 49 percent, HR = 0.71). As a secondary efficacy endpoint nusinersen-treated patients had more positive responding scores (65 percent versus 4 percent) and fewer worsening scores (4 percent versus 48 percent) on CHOP-INTEND than controls. Findings on various electrophysiologic studies and other efficacy endpoints also supported nusinersen. During the review cycle, the applicant provided topline results from the CHERISH study. An analysis of 126 patients (84 on nusinersen and 42 sham controls) found nusinersen-treated patients achieved higher HFMSE scores than controls (4.0 versus -1.9, p= ), and sensitivity analyses consistently supported these findings. More patients treated with nusinersen achieved a 3-point or greater increase in HFMSE scores at 15 months over baseline than controls (57 percent versus 21 percent, p not reported). The study was stopped based on a highly statistically significant treatment effect. Although the Food and Drug Administration had not independently verified these results, they supported approval of nusinersen 8

9 without restriction of age of onset based on interim results of both trials that demonstrated significant and clinically meaningful improvements in motor function and acceptable safety. Since the Food and Drug Administration summary review, the final results of the ENDEAR and CHERISH trials, and interim data from the NUTURE study were presented at the American Academy of Neurology (AAN) 69th Annual Meeting held in April, 2017 (Kuntz, 2017; Mercuri, 2017; De Vivo, 2017; table 2). The final results of the ENDEAR and CHERISH trials are consistent with the interim findings. Nusinersen demonstrated a favorable safety profile, and no children discontinued treatment due to adverse events. The majority of adverse events were considered to be related to spinal muscular atrophy, common events in the general population, or events related to the lumbar puncture procedure. The NUTURE trial (NCT ) is a phase 2, open-label, multicenter, multinational, single-arm study of 20 infants less than six weeks old with genetically diagnosed and pre-symptomatic spinal muscular atrophy with two or three copies of SMN2 (i.e., most likely to develop Type I or II) (De Vivo, 2017; table 2). Infants had been enrolled for a median of (range 2.0 to 524.0) days. Eighty percent of the infants experience an adverse event. Most were not serious, believed to be drug-related, or caused withdrawal from the study. Event-free survival was 100 percent, and infants achieved motor milestones and growth parameters consistent with normal development, but unlikely to be achieved by infants with spinal muscular atrophy Type I or II. Children from the ENDEAR and CHERISH studies are being transitioned into the SHINE open-label extension study (NCT ) for further monitoring. The EMBRACE study (NCT ) is a randomized, doubleblind, sham-procedure controlled study of safety, tolerability, and efficacy of nusinersen in persons with spinal muscular atrophy who are not eligible to participate in either the ENDEAR or CHERISH study. Policy updates: We added two peer-reviewed publications to this policy in Summary of clinical evidence: Citation De Vivo (2017) for Biogen NUTURE study: interim results Content, Methods, Recommendations Key points: Phase II, open-label, multicenter, multinational, single-arm study of 20 infants < 6 weeks old with genetically diagnosed spinal muscular atrophy, pre-symptomatic at treatment initiation, and two (n=13) or three (n=7) copies of SMN2. Primary endpoint=event survival (time to death or respiratory intervention) and HINE-2 motor milestone achievements. Event survival = 100% at a median days (range 2.0 to days). Continued beneficial effects of nusinersen in infants with presymptomatic spinal muscular atrophy on survival and achievement of motor milestones over the expected natural history of spinal muscular atrophy type I. Most infants achieved motor milestone and growth parameter gains generally 9

10 Citation Kuntz (2017) for Biogen ENDEAR Study: final results Mercuri (2017) for Biogen CHERISH study: final results NCT ISIS CS4 Content, Methods, Recommendations consistent with normal development, such as head control, independent sitting, standing, and walking independently. Eighty percent of patients experienced adverse events, but none involved specific safety concerns or withdrawals from the study. Key points: Phase III study of 110 total participants with a genetic diagnosis of spinal muscular atrophy, two copies of the SMN2 gene, onset of spinal muscular atrophy symptoms at age six months and age seven months with no hypoxemia at screening. Primary endpoints: - Proportion of motor milestone responders from day 183 onward using HINE- 2. (Responder = more HINE categories with improvement than worsening; 2-point change in ability to kick). HINE-2: 51 percent versus 0 percent (P < ) - Event-free survival (intention to treat population at end of study) favored nusinersen (HR 0.53, P=0.0046) Secondary endpoints included: - CHOP INTEND responders 4-point improvement from baseline in total score from Day 183 onward: 71 percent versus 3 percent (P < ) - Proportion of CMAP responders (peroneal nerve) maintenance or increase by 1 mv versus baseline from day 183 onward. - Time to death or permanent ventilation. Overall survival favored nusinersen (Hazard Ratio 0.372, P = ). The risk of permanent ventilation: favored nusinersen: 34 percent lower (Hazard Ratio 0.66, P = ). - Peroneal CMAP responders: 36 percent versus 5 percent (P = ) Statistically significant improvement with nusinersen versus sham in primary and secondary outcome measures. Infants treated with nusinersen achieved motor milestones unexpected for infants with spinal muscular atrophy type I. Nusinersen was well tolerated and no safety concerns were identified: - No adverse events (AEs) were considered related to treatment. - All AEs that led to discontinuation were AEs with fatal outcomes. - Commonly reported AEs were consistent with those expected in the general population of infants with spinal muscular atrophy. Key points: Phase III, randomized, double-blind, sham-controlled study of 126 patients (84 on nusinersen, 42 controls) with type 2 spinal muscular atrophy; 88% had three copies of the SMN2 gene [range: two to four), and onset of clinical signs and symptoms consistent with spinal muscular atrophy at > age six months.nusinersen-treated children demonstrated significant and clinically meaningful improvements in motor function vs. sham based on HFMSE and WHO motor development milestones measures. HFMSE score change from baseline: +3.9 points versus -1.0 points (P = ). New World Health Organization motor milestone responders at Month 15: 5.9 percent (95 percent confidence interval [CI] 0.7 to 19.7) versus 19.7 percent (95 percent CI 10.9 to 31.3) (P=.0811) Treatment-emergent AEs, severe AEs, and serious AEs (SAEs) were reported less 10

11 Citation Luu (2017) Population pharmacokinetics of nusinersen in the CSF and plasma of pediatric patients with spinal muscular atrophy following intrathecal administrations Chiriboga (2016) NCT and NCT Safety, tolerability, PKs, and preliminary clinical efficacy of nusinersen Finkel (2016) Content, Methods, Recommendations frequently in nusinersen-treated versus controls. Most frequent AEs were back pain, headache, and vomiting, and occurred at a 5% higher frequency in the nusinersen group 72 hours following drug administration, likely related to the lumbar puncture procedure. No evidence of adverse effects on platelet counts, renal function, or hepatic enzymes. Children from CHERISH are being transitioned to the SHINE open label extension1 Key points: Population-based modeling study of 72 pediatric patients (3 months to 17 years) with spinal muscular atrophy across five clinical trials. The model predicted that the CSF volume of distribution increased steadily with age from 0 to 2 years but became relatively steady for children >2 years. Simulations from the final model showed that age-based dosing in children < 2 years ensured a more comparable exposure (peak concentration and area under the concentration-time curve) across subjects relative to a fixed dosing scheme. A fixed-dose scheme (12 mg across all age groups) was recommended, because no dose-limiting toxicity has been reported in any of the trials. The median terminal half-life of nusinersen in the CSF was 163 days, which supported infrequent dosing, once every four to six months in pediatric patients with spinal muscular atrophy. Key points: Open-label phase I study and extension study of 28 medically stable patients with symptomatic.type 2 and type 3 spinal muscular atrophy ages 2 to 14 years with documented SMN1 homozygous gene deletion. Other criteria were the ability to complete all study procedures, meet age-appropriate institutional guidelines for LP procedures, and have a life expectancy of > 2 years per investigator judgment. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of six to ten participants. Efficacy endpoints = HFMSE and Pediatric Quality of Life Inventory scores: clinically meaningful change in HSMSE = 3 points over a six-month period. Plasma and CSF drug levels were dose-dependent; CSF drug half-life = four to six months after initial clearance. Safe and well-tolerated. Most patients experienced AEs, but no serious AEs during the course of the study, and no participant experienced an AE leading to discontinuation. No immunogenic response to nusinersen observed at nine to 14 months after a single intrathecal dose. Significant increase in HFMSE scores at the 9-mg dose at 3 months post-dose (3.1 points; p = 0.016), which increased nine to 14 months post-dose (5.8 points; p = 0.008) during the extension study. Pediatric Quality of Life Inventory: no statistically significant differences. No clinically significant abnormalities on neurologic examinations or laboratory safety assessments, including CSF safety assessments at 7 or 28 days and 9 14 months post-dose. Key points: ClinicalTrials.gov, number NCT Phase ll, open-label, dose-escalation study of 20 patients with infantile-onset spinal muscular atrophy ages 3 weeks 7 months old with onset of spinal muscular atrophy 11

12 Citation ISIS CS3A Safety and tolerability, PK, and clinical efficacy of multiple intrathecal doses of nusinersen (6 mg and 12 mg dose equivalents) for treatment of infantile-onset spinal muscular atrophy Hache (2016) NCT and NCT Dose escalation study of nusinersen intrathecal injections in children with spinal muscular atrophy: experience Content, Methods, Recommendations symptoms between three weeks and six months and with SMN1 homozygous gene deletion or mutation. Safety assessments included adverse events, physical and neurological examinations, vital signs, clinical laboratory tests, CSF laboratory tests, and electrocardiographs. Clinical efficacy endpoints: event free survival; HINE-2 and CHOP-INTEND at baseline and last visit; and compound motor action potentials (CMAPs). Autopsy tissue was analyzed for target engagement, drug concentrations, and pharmacological activity. Seventy-seven serious adverse events were reported in 16 participants, all considered not related or unlikely related to the study drug. In the 12 mg dose group, incremental achievements of motor milestones (p<0.0001), improvements in CHOP-INTEND motor function scores (p=0.0013), and increased CMAPs amplitude of the ulnar nerve (p=0.0103) and peroneal nerve (p<0.0001) from baseline were observed. Median age at death or permanent ventilation was not reached and the Kaplan-Meier survival curve diverged from a published natural history case series (p=0.0014). Autopsy analysis of tissue from patients exposed to nusinersen showed drug uptake into motor neurons throughout the spinal cord and neurons and other cell types in the brainstem and other brain regions, exposure at therapeutic concentrations, and increased SMN2 mrna exon 7 inclusion and SMN protein concentrations in the spinal cord. Key points: Phase I open-label study of nusinersen and its extension study of 73 lumbar punctures in 28 patients ages 2 to 14 years with types 2/3 spinal muscular atrophy and a life expectancy of >2 years. Exclusion criteria: serious respiratory insufficiency, hospitalization for surgery or pulmonary event within the past two months, active infection at screening, history of brain or spinal cord disease or bacterial meningitis, presence of implanted CSF drainage shunt, clinically significant laboratory abnormalities, any ongoing medical condition that would interfere with the conduct and assessments of the study, treatment with another investigational drug within one month of screening, or scoliosis if an LP could not be performed safely. Adverse events occurred in 23 (32%) procedures, most common were headache (n = 9), back pain (n = 9), and post-lp syndrome (n = 8); more frequent in older children, children with type 3 spinal muscular atrophy, and with a 21- or 22-gauge needle compared to a 24-gauge needle or smaller. References Professional society guidelines/other: ACOG Committee Opinion No. 691 Summary: Carrier Screening for Genetic Conditions. Obstet Gynecol. 2017; 129(3):

13 De Vivo DC, Hwu W-L, Reyna SP, et al. on behalf of the NURTURE Study Group. Interim Efficacy and Safety Results from the Phase 2 NURTURE Study Evaluating Nusinersen in Presymptomatic Infants With Spinal Muscular Atrophy. Paper presented at: American Academy of Neurology 69th Annual Meeting. April 22 28, 2017; Boston, MA. Biogen website. NURTURE_Interim_Results_Presentation_Ph3_AAN_2017.pdf. Accessed April 26, Kang PB, Morrison L, Iannaccone ST, et al. Evidence-based guideline summary: evaluation, diagnosis, and management of congenital muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology. 2015; 84(13): Kuntz N. Finkel RS, Mercuri E, et al. Final Results of the Phase 3 ENDEAR Study Assessing the Efficacy and Safety of Nusinersen in Infants With Spinal Muscular Atrophy (SMA). Paper presented at: 69th Annual Meeting of the American Academy of Neurology. April 22 28, 2017; Boston, Massachusetts. Biogen website. ENDEAR_Final_Results_Presentation_Ph3_AAN_2017.pdf. Accessed April 26, Mercuri E, Finkel R, Kirschner J, et al. on behalf of the CHERISH Study Group. Efficacy and Safety of Nusinersen in Children With Later-Onset Spinal Muscular Atrophy (SMA): Results of the Phase 3 CHERISH Study. American Academy of Neurology 69th Annual Meeting; April 22 28, 2017; Boston, Massachusetts. Biogen website. CHERISH_Final_Results_Poster Presentation_Ph3_AAN_2017.pdf. Accessed April 26, U.S. National Library of Medicine. Spinraza. ClinicalTrials.gov website. y=&dist=. Accessed April 26, Wang CH, Finkel RS, Bertini ES, et al. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol. 2007; 22(8): Peer-reviewed references: Burgart AM, Magnus D, Tabor HK, et al. Ethical challenges confronted when providing nusinersen treatment for spinal muscular atrophy. JAMA Pediatr. 2018;172(2): Center for Drug Evaluation and Research Application Number: orig1s000. Summary Review. Food and Drug Administration website. Accessed April 25,

14 Chiriboga CA, Swoboda KJ, Darras BT, et al. Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. Neurology. 2016; 86(10): Farrar MA, Kiernan MC. The Genetics of Spinal Muscular Atrophy: Progress and Challenges. Neurotherapeutics. 2015; 12(2): FDA Product label. SPINRAZA (nusinersen) injection, for intrathecal use. Initial U.S. Approval: Food and Drug Administration website. Accessed April 25, Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016; 388(10063): For Industry. Developing Products for Rare Diseases & Conditions. Last updated April 18, Food and Drug Administration website. Accessed April 25, Genetics Home Reference. Spinal muscular atrophy. April 25, U.S. National Library of Medicine website. Accessed April 25, Glanzman AM, McDermott MP, Montes J, et al. Validation of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND). Pediatr Phys Ther. 2011; 23(4): Hache M, Swoboda KJ, Sethna N, et al. Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. J Child Neurol. 2016; 31(7): King NMP, Bishop CE. New treatments for serious conditions: ethical implications. Gene Ther. 2017;24(9): Kolb SJ, Kissel JT. Spinal Muscular Atrophy. Neurol Clin. 2015; 33(4): Lin CW, Kalb SJ, Yeh WS. Delay in Diagnosis of Spinal Muscular Atrophy: A Systematic Literature Review. Pediatr Neurol. 2015; 53(4): Luu KT, Norris DA, Gunawan R, et al. Population Pharmacokinetics of Nusinersen in the Cerebral Spinal Fluid and Plasma of Pediatric Patients With Spinal Muscular Atrophy Following Intrathecal Administrations. J Clin Pharmacol Main M, Kairon H, Mercuri E, Muntoni F. The Hammersmith functional motor scale for children with spinal muscular atrophy: a scale to test ability and monitor progress in children with limited ambulation. Eur J Paediatr Neurol. 2003; 7(4):

15 Munsat, TL. Workshop report International SMA Collaboration. Neuromuscul Disord. 1991; 1(81). O'Hagen JM, Glanzman AM, McDermott MP, et al. An expanded version of the Hammersmith Functional Motor Scale for SMA II and III patients. Neuromuscul Disord. 2007; 17(9-10): Sardone V, Zhou H, Muntoni F, Ferlini A, Falzarano MS. Antisense Oligonucleotide-Based Therapy for Neuromuscular Disease. Molecules. 2017; 22(4). Simone C, Ramirez A, Bucchia M, et al. Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications? Cell Mol Life Sci. 2016; 73(5): Tisdale S, Pellizzoni L. Disease mechanisms and therapeutic approaches in spinal muscular atrophy. J Neurosci. 2015; 35(23): Wadman RI, Bosboom WM, van der Pol WL, et al. Drug treatment for spinal muscular atrophy type I. Cochrane Database Syst Rev. 2012; (4): Cd Wadman RI, Bosboom WM, van der Pol WL, et al. Drug treatment for spinal muscular atrophy types II and III. Cochrane Database Syst Rev. 2012; (4): Cd CMS National Coverage Determinations (NCDs): No NCDs identified as of the writing of this policy. Local Coverage Determinations (LCDs): No LCDs identified as of the writing of this policy. Commonly submitted codes Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill accordingly. CPT Code Description Comments Spinal puncture, lumbar, diagnostic Spinal puncture, therapeutic, for drainage of cerebrospinal fluid (by needle or catheter Injection(s), of diagnostic or therapeutic substance(s) (eg, anesthetic, antispasmodic, opioid, steroid, other solution), not including neurolytic substances, including needle or catheter placement, interlaminar epidural or subarachnoid, lumbar or sacral (caudal); without imaging guidance Injection(s), of diagnostic or therapeutic substance(s) (eg, anesthetic, 15

16 CPT Code Description Comments antispasmodic, opioid, steroid, other solution), not including neurolytic substances, including needle or catheter placement, interlaminar epidural or subarachnoid, lumbar or sacral (caudal); with imaging guidance (ie, fluoroscopy or CT) Fluoroscopic guidance and localization of needle or catheter tip for spine or paraspinous diagnostic or therapeutic injection procedures (epidural or subarachnoid) (List separately in addition to code for primary procedure) Ultrasonic guidance for needle placement (eg, biopsy, aspiration, injection, localization device), imaging supervision and interpretation Intravenous infusion administration Unlisted therapeutic, prophylactic, or diagnostic intravenous or intra-arterial injection or infusion Chemotherapy administration, into CNS (eg, intrathecal), requiring and including spinal puncture ICD-10 Code Description Comments G12.0 Infantile spinal muscular atrophy, type I [Werdnig-Hoffman] G12.1 Other inherited spinal muscular atrophy G12.8 Other spinal muscular atrophies and related syndromes G12.9 Spinal muscular atrophy, unspecified HCPCS Level II Code J3490 J3590 Description Unclassified drugs Unclassified biologics Comments Appendix. Perform Rx prior authorization criteria for Spinraza Prior Authorization Group Description: Spinraza Drugs: Spinraza (nusinersen) Covered Uses: Medically accepted indications are defined using the following sources: the Food and Drug Administration (FDA), Micromedex, American Hospital Formulary Service (AHFS), United States Pharmacopeia Drug Information for the Healthcare Professional (USP DI), the Drug Package Insert (PPI), or disease state specific standard of care guidelines. Exclusion Criteria: N/A Required Medical Information: See Other Criteria Age Restrictions: N/A 16

17 Prescriber Restrictions: Prescriber must be a neurologist Coverage Duration: If all of the conditions are met, the request will be approved for 5 doses (4 loading doses and 1 st maintenance dose). Reauthorizations will be approved for 12 months. If the conditions are not met, the request will be sent to a Medical Director/clinical reviewer for medical necessity review. Other Criteria (Revision/Review Date 1/2018): For Approval: Member has confirmed diagnosis of spinal muscular atrophy (SMA) types I, II or III, and the molecular genetic test with mutation analysis was submitted that is positive for the genetic deletion of the exon 7 of the survival motor neuron (SMN1) gene Baseline motor function or motor milestone achievement was submitted with request [e.g. CHOP Infant Test of Neuromuscular Disorders (CHOP-INTEND) for Type 1 or Hammersmith Functional Motor Scale Expanded Scores (HFMSE) or Hammersmith Infant Neurological Examination (HINE) for Type II and Type III] Baseline labs values were submitted with request (within 30 days of request) for the following labs: complete blood count (CBC) prothrombin time and activated partial thromboplastin time spot urine protein test The request is for an FDA approved dose Reauthorization: Documentation of clinical response based on the prescriber s assessment was submitted with request (e.g. improvement in motor function/motor milestone achievement scores using CHOP- INTEND, HFMSE or HINE. improvement in more categories of motor milestones than worsening), patient remains permanent ventilation free) Repeat labs were submitted with request (listed above, within 30 days of request) The request is for an FDA approved dose Physician/clinical reviewer must override criteria when, in his/her professional judgement, the requested item is medically necessary. 17